Substituted 1,3,5-triazinyl-(6)-aminophenyl-arsenic compounds



Patente d June 24, 1947 UNITED STATES PATENT soes'ri'ro'rnn1,3,5-TRIAZiNX (e- Amne- PHENYL-ARSENIC'COMPOUNDS Ernst A. H. Friedheim,New York, N. Y.

N Drawing. Application January '20, 1944, Serial No. 518,998

7 Claims.

This inventionrelates to derivatives 'o'f'triazines containing arsenic,and more particularly to triazine derivatives which contain trivalentarsenic.

In my U. S. Patent 2,295,574, issued on September 15, 1942, I have shownthat condensation of suitable derivatives of symmetric triazine withphenyl-arsonic acid derivatives results in a new type of condensationproducts possessing valuable therapeutic properties in diseases causedby spirochaetes or trypanosomes, such as syphilis, and African sleepingsickness.

I have found that "new triazine derivatives-containing arsenic can beobtained by condensing derivatives of 1,3,5-triazine of the formula withan aromatic organic compound containing trivalent arsenic andcorresponding to the formulalw -jCeHzflAfl B) AS'X. v in v In h e am ean m eam or halogen. Ii W is an amino-group, 'at leastone of 'vne greupsD, E, F is a halogen-group. If W is a haldg'en, at least one of thegroups 11 E, F is amino group, In both cases the othergi'oup'sareselected from the group consisting of halogen, All N Alkz,hydroXy-alkylam'in NH HCHO CH-ZOH, 'dialkyl-amino-al sy at, andaminoacyl radicals, such as Nndocm and NI-ICOC'sI-Is; the radicals A andB are selected from the group consisting of hydrogen, halogen, OH, OA111, 0 acyl, N02, NHz, NH Alk., N A1122, aminoacyl, and alkyl radicals;X is a divalent group selected from the group consisting of O, s,dihalides, such as 012, I2 or Em, and sulfur-containing radicals of type(S-'R)2 wherein R is an organic radical which is capable of carrying an'SH-radical'. Such :suI- fur-containing reactants are, for example,thioglycollic acid, cysteine, or glutathione,thiophenol, thioaceticacid, thiobenzoic acid, thidacetamide, thiosalicylic acid,p-sulfhydriI-benzene -su1foni'c acid, thiopropi-onic acid, psulfhydrilphenylacetic acid. As examples of the trivalent arseniccompounds to be used according to my invention, the following may bementioned: l -aminophenylarsinoxide, 4chlorr-phenylarsinoxide, 4-amino-phenylarsindichloride,, -amino-phenyl arsi'nsulfide, 3-amino 4oxy-phenylarsinoxide.

--2 The condensation products thus formed have the formula 'YQ'J' g NHoJHi(A,B)'=As='X' wherein Y and Y are .each a riadical selected from thegroup consisting of halogen, NI-In, NH A1k., N Alk.z,hydroxy-allcyl-iamino,

uncmcnoncnto-n I a n m a manac awn-an 31s: A drB. re ele ted tem th r up01;- i sef yd n l en O 04 1 0 n N0 NHa N i el -1,1? .anflnQ- 1 ..ans ely' ra i als n a imle t a ,se ecte rqm iheqs un 9 st n oi a dih id uli re e ni l llpi oiuihemi e $1 9 1 w sre nfi, s as. r ani radipal .whiqn. ifia ahle of carrying a SH-r'adical, and groups having the formulaSubsequently, this reaction product may be treated with a loaseselecte'dfrom the group consisting of ammonia, alkyl amines, hydfo'z'iygalkylamines and dialkyl-amino-alkyl amines. Similar reactions may be obtainedby using a dihalide such as 4-amino-phenylarsindich1oride instead of 4-oxy-3-amino-phenylarsinoxide Instead of the latter, its derivatives orisomers, such (as, for instance, 2-oXy-4-amino-phenyl-arsinoxide, or 4-amino-3-oxy-phenylarsinoxide may also be used. In carrying out thesereactions, instead of the trichloro-triazine other derivatives of,3,5-triazine corresponding to the formula referred to above may also beused.

I have further found that the condensation products according to thisinvention may also be obtained by first forming a condensation productof the type disclosed in my above mentioned U. S. Patent No. 2,295,574from a derivative of 1,3,5-triazine and a substituted phenyl-arsonicacid, and converting the condensation product thus obtained, into acompound containing'trivalent arsenic. -I have found that suchconversion can be performed without the disintegration of the basictriazinyl-aminobenzene structure by treating the triazinyl-aminobenzene-'arsonic acid condensation product in hydrochloric acid solution, in thepresence of hydriodic acid, with S02, hypophosphorous acid (HzPOs), orstannous chloride, or in neutral or alkaline solution withphenyl-hydrazine or sodium hydrosulfite (Na2S2O4). The reduction withS02 or phenylhydrazine leads to the arsinoxides or dihalogenarsines,while the treatment with stannous chloride, hypophosphorous acid, andsodium hydrosulfite leads to the corresponding arsenocompounds.

For example, one part by weight of 2,4-diamino 1,3,5 triazinyl- (6)[amino 3-oxy-4- phenylarsonic acid I] is dissolved atabout 80 C. in 100parts of hydrochloric acid of sp. gr. 1.19. To the clear, warm solution6 part of sodium iodide is added, and a stream of S02 gas is allowed topass through the solution. After a few minutes the solution becomescloudy, and the hydrochloride of 2,4-diamino-1,3,5-triazinyl- (6)oxyaminophenylarsindichloride separates out in crystalline form. Itis'soluble in' ethyl alcohol from which it maybe recrystallized; It isslight ly soluble in acetone, and insoluble in chloroform, C-Cl4 andbenzene. The corresponding arsinoxide is formed by the action of alkali,such as dilute ammonia or sodium bicarbonate on the arsindichloride.

An arseno-com'pound can be obtained by the action of stannous chlorideon 2,4-diamino-triaziny1-(6)-[4-oxy-3-amino phenylarsonic acid I]. Onepart of the latter is suspended in 50 parts of aqueous hydrochloric acidof 1.19 density containing about 50% stannous chloride, and 1% ofhydriodic acid. On gentle warming the substance goes slowly intosolution, the reaction mixture taking a yellow color. It becomes cloudy,and on standing a yellow precipitate separates, which represents thehydrochloride of the bis [2,2'-4,4'stetraamino-triazinyl (6-6') (3 3'diamino-4-4' dioxyarseno-benzene) of the formula:

4 This compound is moderately soluble in dilute hydrochloric acid andinsoulble in ether and chloroform.

Other compounds according to my present invention may be obtained byapplying the above described reduction processes to otherarsenoanilino-triazine compounds, such asmonochlormonoamino-arsono-anilino-triazine, and otherarsono-anilino-triazine compounds obtained according to my abovementioned U. S. Patent No.

As described in Example 2 of my U. S. Patent 2,295,574 p-[2,4= dichloro1,3,5-triazinyl-(6)] aminophenyl-arsonicacid may be treated with ammoniain order to convert it into a 2-chloro i-amino-compound by covering saiddichloro compound with 10 times the quantity of 10% aqueous ammonia, andshaking at 45 C. for 1 hour, whereby the product goes into completesolution. By heating the [2-chloro-4-amino 1,3,5-triaziny1 (6)l-aminophenylarsonic compound in hydrochloric acid solution with S02, acompound having the formula:

G-NH-C AS=O may be obtained.

Compounds corresponding to the general formula may be prepared bycondensing a substituted phenyl-thioarsinite with a suitable triazinederivative, for example an aminophenylthioarsinite and cyanuric chlorideor by reacting a compound of the formula I-ISR with a suitable triazinederivative carrying an aminophenyl radical containing arsenic. One molof a triazine derivative carrying an aminophenylarsonic acid group maybe reacted with 4 mols of the HSR-type compound, the latter causingfirst a reduction of the pentavalent arsenic radical to a trivalentarsenic radical and then combining in situ with the trivalent arsenic toa compound containing an As=(SR.)2 type radical. Or a triazinederivative containing an aminophenylAs type radical, such asaminophenyl-As=0 or As=Cl2 may be prepared in a first step, and.

uct is separated by the addition of ethyl alcohol s: and dra nasi: w 1 1.11;em url i- 'li is: med an. product has the formula:

a %C\ OE r r HzN-Q O-NHG N As: SGHgCHNH-COCHzOHzCH-NH;

I: CON'HGHZOOOH c0011 1 The compound" thus obtained issoluble. inaqueous solutions of: sodium hydroxide or so dium carbonateandtsparinglysoluble in an. excess of dilute mineral acid It can. beprecipitated from alkaline solutions by acidifying said solutions.

Cystein hydrochloride maybereacted withp- (2,4 diamino triazinyl -(6) [4oxy-3-aminophenylarsinoxide] according to the following scheme:

N inqsonmnmna o on In order to carry out this reaction, the above namedphenylarsinoxide (4.0' g.) was added to an aqueous solution of, 3.0, g.cysteine hydrochloride in 50 g. of water. On moderate warming andstirring, a clear solution is obtained. To the solution sodium carbonateis then added until sncutral tofl ngorapen- Tneneutrmsomtmn smixedwthwcc.qf abs ut alcohql nd came q/ out ?:3" C Qr-a f w q r l e a at h cde aticn; ro u t rom he luti n-4 h and bstan e s e ar te mm th iquid yltration w shed, with; ,05%- e ue s' cch ll It nsq ubl ther; blami rmand ceWncansisdubh naquwus sedium a h nate ent ent.

The, bove ea tion. et eenhcysteine,b 41 0: loride and r-i A- am npr riny rfil -ler oxy-3 amino-phenylarsino delmay also be carried out byreacting in an alcoholic reaction medium under stirring a mixture oicysteine hydrochloride, water, NaHCOs and said phenylarsinoxide or byheating said reaction mixture to boiling temperature for a few minutesuntil a clear solution is obtained, and then making the solutionslightly acid to Congo paper. The reaction product is soluble in aqueoussolutions of N aHCOa, NazCOa, or NaOH.

A water-soluble compound of the formula may be obtained by reacting.p-[.2,4 d imethylamino-l,3,5-triazinyl- (6) l aminophfinyl-afsindichloride with potassium thioglycolate. In order to obtain thiscompound, 3.5: g. of said: arsindie chloride is added to an aqueoussolution; containi -5 a. of potassium thicglyco atewandth m vmir rleratel;henna,and he n neteenth NaHCOa to tralize he; hydrcchlqriq sidformed. A similar compound may be obtained from potassium thioglycolateand p[2,4-diamino- 1,3,5 triazinyl (6) l- 4 oxy 3amino-phenylarsindichloride.

If in the above reaction the, sodium salt of thiosalicylic acid is usedinstead of potassium thioglycolate in a substantially similar manner, awater-soluble compound of the formula n N N, I Neil-( -NnC 'As=s,o@H1-ocom):

is obtained,

In reacting 1,3,5-triazinyl-aminophenyl-arsonic acid compounds withcompounds carrying the SH group, 1 mol of the arsonic acid compoundrequires the use of 4 mols of the mercapto compound, For example, 4 molsof thioglycollic acid are dissolved in a 10 %,aqueous NaQH solution andreacted with one mol of [2,4-dimethylamin0- .1,3;5.-triaZ-iny1- 163l-3.-amino- 41 -hydroxy-V phenyl-varsonic acid, and the reactionproductis precipitatedby acidifying the solution. On .m0l ofsaid-arscnic acidis added. to an aqueous solu tioncontaining /2 mol of cysteine.hydrochloride andheated to 80'-.90?"C. After thereaction, the solutionis neutralized; with NaI-IQOs.

A condensation. product of p-su1fhydrilbenzene sulfonic acid and?2-,4,-amino-.1,3,5-triazinyl-(6).- aminophenyl. arsinoxide. may be,obtainedby 1 dis.

" solving. said; benzenesulfonic acid in. ethyl alcohol and reacting thealcoholic solution under stirringwith an alcoholic suspension of saidarsinoxide. The reaction takes place according to the following scheme:

, a This condensation product is scarcely soluble in is obtained. Theproduct is soluble in aqueous allgaliapgl; can be precipitated from itsalkaline solution by theaddition of acetic acid. v

An alcoholic solution containing /2 mol of-thiopropionic acid(HSCH2CH2COOH) may be reacted under-st rrin with an alcoho ic su pens on0i 1% mol: of ZrfiIQiHOeFk diIIlQthYlrLIIliIlQ-1,3,5-triazinyl-(Si-aminophenylarsonic acid to form a compound of theformula This compound can be dissolved in aqueous solutions of NazCOa orNaOH and precipitated by means of acetic acid from such solutions.

By reacting a 2% aqueous solution containing /2 mol of a-thiolacetami'dewith mol of 2- chlorol-amino-1,3,5-triazinyl- (6) -amino phenylarsonicacid added to said solution in a finely divided state under stirring areaction product is formed, which corresponds to the formula Thereaction product can be dissolved in an excess of strong aqueous sodiumhydroxide.

An aqueous alkaline solution containing Ts mol of2,4-diamino-1,3,5-triazinyl- (6) [amino-3-oxy- 4phenylarsinoxide]prepared in the above described manner by reduction of the correspondingarsonic acid compound with S02 gas and treatment of the arsindichlorideformed with sodium bicarbonate, may be reacted with 1% mol of thiophenolunder stirring for about 24 hours in order to form a, compoundcorresponding to the formula Instead of thicphenol an equivalent amountof a-thionaphthol may be used in a substantially similar manner. Bytreating an aqueous solution of the condensation products with a mildoxidizing agent, such as H202, the corresponding triazinyl arsonic acidsand symmetrical disulfides are formed.

A compound correspondin to the formula C1 COOH may be prepared bycondensing 1 mol of 3-chlorol-amino-phenylarsinoxide and 2 /4 mols ofo-thiol-benzoic acid in alcoholic solution under stirring for 18-24hours in a non-oxidizing atmosphere. The compound thus obtained may bereacted with a fine suspension of one mol of cyanuric chloride in waterat a temperature of C. with the exclusion of oxygen. In this reaction analkali soluble triazine derivative corre- "i sponding to the followingformula is formed:

I o 0 OH ab ve reaction 4-amino-3-methyl-phenflar'sln' e may be used ina substantially similar manner in order to form a compound of theformula Condensation of 4-amino-3-acetamino-phenylarsonic acid withcyanuric chloride and reaction of the condensation product thus formedwith an excess of thicphenol in aqueous alkaline solution results in awater-insoluble compound corresponding to the formula By forming acondensation product from 2- chlorol-dimethylamino-phenylarsonic acidand triamino-triazine (melamine) in the above described manner, andreacting one mol of said condensation product with 5 mols of thiophenolin aqueous alkaline solution under stirring the following compound isformed This compound is insoluble in water and scarcely soluble in anexcess of dilute hydrochloric acid.

A condensation product of 4=amino-3-methoxyphenylarsonic acid andcyanuric chloride may be obtained by reacting one mol of said arsonicacid with an aqueous suspension of 1 mol of cyanuric chloride at 0 C. Byreducing the condensation product in hydrochloric acid solution with S02gas and reacting the arsindichloride formed by such reduction with 2mols of potassium thioglycolate a water-soluble compound correspondingto the formula OCHa a r-2am tion takes place "according "to "the -f'ollovv-in scheme:

1|TH2 o An equivalent amount of 6-bromo-2-mercapt0- quinoline may Zb'eused "in "a substantially similar manner instead of 2-mercapto-quinolinein the above reaction. 7 x ,7

Another mercapto-quinoline derivative enibodying the pr'sefit inventionmay "be obtained by dissolving mol of 8-mercapto-quinoline in ethylalcohol and reacting this solutionfvithfi an e .2ie es ar zinviac2 eawarsinO'x'ide for "gamers. Theresulting compound has the formula ilTTHz N N A similar reaction may be carried out in alcoholic reactionmedium by using instead of S-mercaptoquinoline an equivalent amount of2-mercapto-4- methylquinoline, 2mercapto-fi-methylquinoline or2-mercapto-pyridine.

I have also found that by reacting, 2,4 diaminotriazinyl (6)aminophenyl-arsinoxide with an alcoholic solution of,Bphthalimido-ethylmercaptan a reaction product corresponding to thefollowing formula is obtained:

Z-mercapto-pyridine and 4-mercapto-2,6-dimethyl-pyridine may also bereacted with the above aminophenyl-arsinoxide in an alcoholic reactionmedium under stirring and moderate i gage-eraarenas?arrespenaae arreformula ,1 N N I NHfl (-NHO-rfi L S N N J2 and NHL

whamm and Y are each a radical selected firom the group consisting ofhalogen and amino radicals; A and B are selected from the groupconsisting of hydrogen, halogen, hydroxyl, alkyl, and amino radicals,and SR is selected from the group of organic sulfhydril radicalsconsisting of aliphatic, aromatic, pyridine and quinoline sulfhydrilradicals.

2. A method of preparing a triazinyl derivative of the formula 1 t N NYa ps4 N AS=(SR)1 wherein Y and Y are each a radical selected from thegroup consisting of halogen and aminoradicals; A and B are selected fromthe group consisting of hydrogen, halogen, hydroxyl, alkyl, andamino-radicals, and SR is an organic sulfhydril radical, said methodcomprising the step of reacting in a liquid reaction medium a triazinylderivative corresponding to the formula wherein As=X is a radicalselected from the group consisting of AsOaHz, -As=0 and As =dihalide,with an organic sulfhydril compound 1 1 sellectedfrom the. groupconsisting ofaliphatic, aromatic, pyridine and quinoline sulfhydrilcompounds. v a

3. A method as claimed in claim 2, in which one mol of atriazinyl-compound of the formula ASOsHz A B is reacted with at least 4mols of the organic sulfhydril compound selected from the groupconsisting of aliphatic, aromatic, pyridine, quinoline sulfhydrilcompounds.

4. A method as claimed in claim 2, in which one mol of a triazinylcompound of the formula ll AB wherein X stands for a radical selectedfrom the rgroupiconsisting of O and 'dihalides, isreacted with'at leastjtwo 'mols 'of an organic sulfhydril compound selectedzfromthe groupconsisting of aliphatic; aromatic,

5. -A1,3,5'-triazine derivative ofthe formula" 5 i a semen- NB?) coon]6. A 1,3,5-triazine de i ative of the formula '7. A 1,3,5 tria'zinederivative of the formula NH: I

ERNST A. H. FRIEDHEIM. REFERENCES CITED 3? The following references areof record in the file of this patent:

UNITED STATES PATENTS Number Name Date 5 2,295,574 Friedheim Sept. 12,1942 2,203,733 Hamilton May 28, 1940 FOREIGN PATENTS 1 Number CountryDate Great Britain 1928

